This invention relates to pyridazine derivatives useful in the treatment of a variety of conditions mediated by endothelin and to pharmaceutical formulations containing such compounds useful for the treatment of human and non-human mammals.
Endothelin (ET) is a potent vasoconstrictor synthesized and released by endothelial cells. There are three distinct isoforms of ET: ET-1, ET-2 and ET-3, all being 21-amino acid peptides and herein the term xe2x80x98endothelinxe2x80x99 refers to any or all of the isoforms. Two receptor subtypes, ETA and ETB have been pharmacologically defined (see for example H. Arai et al., Nature, 348, 730, 1990) and further subtypes have recently been reported. Stimulation of ETA promotes vasoconstriction and stimulation of ETB receptors causes either vasodilation or vasoconstriction. The main effects of ET are observed in the cardiovascular system, particularly in the coronary, renal, cerebral and mesenteric circulation, and the effects of endothelin are often long-lasting. Stimulation of ET receptors also mediate further biological responses in cardiovascular and non-cardiovascular tissues such as cell proliferation and matrix formation.
Increased circulating levels of endothelin have been observed in patients who have undergone percutaneous transluminal coronary angioplasty (PTCA) (A. Tahara et al., Metab. Clin. Exp., 1991, 40,1235) and ET-1 has been found to induce neointimal formation in rats after balloon angioplasty (S. Douglas et al., J. Cardiovasc. Pharm., 1993, 22 (Suppl 8), 371). The same workers have found that an endothelin antagonist, SB-209670, causes a 50% reduction in neointimal formation relative to control animals (S. Douglas et al., Circ. Res., 1994, 75). Antagonists of the endothelin receptor may thus be useful in preventing restenosis post PTCA. The ETA/B receptor antagonist Bosentan reportedly decreased blood pressure in hypertensive patients (H. Krum et al., New Eng. J. Med., 1998, 338, 784-790). Antagonists of ETB receptors such as BQ-788 have been demonstrated to increase peripheral resistance in man (Hypertension, 1999, 33, 581-585). Thus ETA-selective receptor antagonists are of benefit in hypertension.
Endothelin-1 is produced in the human prostate gland and endothelin receptors have been identified in this tissue (Y. Saita et al., Eur. J. Pharmacol., 1988, 349,123-128). Since endothelin is a contractile and proliferative agent, endothelin antagonists are useful in the treatment of benign prostate hypertrophy.
There is widespread localization of endothelin and its receptors in the central nervous system and cerebrovascular system (R. K. Nikolov et al., Drugs of Today, 1992, 28(5), 303) with ET being implicated in cerebral vasospasm, cerebral infarcts, septic shock, myocardial infarction and neuronal death.
Elevated levels of endothelin have also been observed in patients with: recurrent airway obstruction (Pulm. Pharm. Ther., 1998, 11: 231-235); asthma (Am. J. Resp. Crit. Care Med., 1995, 151:1034-1039); acute renal failure (K. Tomita, et al., Med. Philos., 1994, 13(1), 64-66); chronic renal failure (F. Stockenhuber et al., Clin. Sci. (Lond.), 1992, 82, 255); ischemic Heart Disease (M. Yasuda, Am. Heart J., 1990, 119, 801); stable or unstable angina (J. T. Stewart, Br. Heart J., 1991, 66, 7); pulmonary hypertension (D. J. Stewart et al., Ann. Internal Medicine, 1991, 114, 464); congestive heart failure (R. J. Rodeheffer et al., Am. J. Hypertension, 1991, 4, 9A); preeclampsia (B. A. Clark et al., Am. J. Obstet. Gynecol., 1992, 166, 962); diabetes (A. Collier et al., Diabetes Care, 1992, 15 (8), 1038); Crohn""s disease (S. H. Murch et al., Lancet, 1992, 339, 381); and atherosclerosis (A. Lerman et al., New Eng. J. Med., 1991, 325, 997).
In every case the disease state associated with the physiologically elevated levels of endothelin is potentially treatable with a substance which decreases the effect of endothelin, such as an endothelin receptor antagonist, or a compound which binds endothelin such that it reduces the effective concentration thereof at the endothelin receptors.
Compounds that antagonise the ETA receptor to a greater extent than the ETB receptor are preferred as ETA receptors are predominantly present in vascular smooth muscles. Blockade of ETB receptor activation may reverse endothelial dependent vasodilation which is beneficial in hypertension. ET may also mediate regeneration of damaged tissue via the ETB receptor, such as proximal tubule cells in the kidney. Thus blockade of ETB receptors, e.g. with a non-selective ET antagonist could inhibit tissue repair. ETB receptors are also involved in the clearance of ET from the systemic circulation. Increased levels of ET are generally considered detrimental. Rises in circulating levels have been observed with non-selective ET antagonists. Treatment with selective ETA receptor antagonists are not likely to induce such rises in circulating levels.
There are a number of publications relating to N-(pyrimidin-4-yl) sulfonamide derivatives having endothelin binding/antagonist activity, for example EP-A-0743307, EP-A-0658548, EP-A-0633259, EP-A-0882719, WO-A-96/20177, EP-A-0801062, WO-A-97/09318, EP-A-0852226, EP-A-0768304, WO-A-96/19459, WO-A-98/03488, EP-A-0601386, EP-A-0510526 and EP-A-0713875.
Various N-4-pyrimidinyl sulfonamide derivatives possessing endothelin antagonist activity are described in JP-A-09059160, JP-A-10194972 and JP-A-10226649.
International Patent Application publication number WO-A-96/19455 discloses phenyl and pyridin-4-yl sulfonamides as endothelin antagonists.
According to the present invention, there are provided compounds of formula (I) 
wherein
R1 is (CR7R8)nxe2x80x94(C3-C8)cycloalkyl, (CR7R8)nxe2x80x94heterocycle, (CR7R8)n-(benzofused heterocycle), (CR7R8)n-aryl, NR9R10, (CR7R8)n-heteroaryl, and (CR7R8)n-(benzofused heteroaryl), where R7 and R8 are each independently H or (C1-C6)alkyl, R9 and R10 are each independently H or (C1-C6)alkyl optionally substituted by aryl, heterocycle, benzofused heterocycle, heteroaryl, benzofused heteroaryl, or (C3-C8)cycloalkyl, and n is 2, 3, 4, 5, or 6;
R2 is (a) phenyl optionally fused with a heterocycle, benzofused heterocycle, heteroaryl, or benzofused heteroaryl, (b) naphthyl optionally fused with a heterocycle, benzofused heterocycle, heteroaryl, or benzofused heteroaryl, or (c) heteroaryl or benzofused heteroaryl, where groups (a), (b) and (c) are optionally substituted by (C1-C6)alkyl, (C1-C6)alkoxy, halo, unsubstituted heterocycle, unsubstituted benzofused heterocycle, unsubstituted heteroaryl, unsubstituted benzofused heteroaryl, phenyl, naphthyl, CO2R11, OC(O)R11, CONR11R12, or S(O)pR11, where p is 0, 1, or 2, and R11 and R12 are each independently H or (C1-C6)alkyl;
R3 is (e) (C1-C6)alkyl, (f) (C2-C6)alkenyl, (g) (C2-C6)alkynyl, or (h) (C3-C8)cycloalkyl, where groups (e), (f), (g) and (h) are optionally substituted by OR11, halo, NHC(O)(C1-C6)alkyl, O-heterocycle, O-(benzofused heterocycle), O-heteroaryl, O-(benzofused heteroaryl), OC(O)NH-heterocycle, OC(O)NH-(benzofused heterocycle), OC(O)NH-heteroaryl, OC(O)NH-(benzofused heteroaryl), NH2, NHC(O)O-heteroaryl, NHC(O)O-(benzofused heteroaryl), NHC(O)NH-heteroaryl, or NHC(O)NH-(benzofused heteroaryl);
X is O, NH, a direct link, or S(O)p, where p is 0, 1 or 2;
Y is O, NH, or S(O)p, where p is 0, 1 or 2; and
R4, R5 and R6 are each independently selected from the group consisting of H, halo, heterocycle, benzofused heterocycle, heteroaryl, benzofused heteroaryl, aryl, (C1-C6)alkoxy, (C1-C6)alkyl optionally substituted by halo, OR9 or NH2, and S(O)pR9, where p is 0, 1 or 2;
a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, a solvate or the compound, salt or prodrug, or a polymorph of the compound, salt, prodrug, or solvate. Processes for making compounds of formula (I) and key intermediates are also provided and described in more detail below.
In another embodiment of the present invention, a pharmaceutical composition is provided comprising (a) a compound of the present invention; and (b) a pharmaceutically acceptable diluent, carrier or adjuvant.
In yet another embodiment of the present invention, a method for treating a condition or disease mediated by an endothelin receptor (in particular, an EtA receptor) is provided comprising the step of administering to a patient in need of such treatment a therapeutically-effective amount of a compound of the present invention. In particular, the method is useful for the prevention or treatment of conditions or diseases selected from the group consisting of restenosis, acute or chronic renal failure, pulmonary hypertension, systemic hypertension, benign prostatic hyperplasia, male erectile dysfunction, prostate cancer, metastatic bone cancer, congestive heart failure, stroke, subarachnoid haemorrhage, angina, atherosclerosis, cerebral and cardiac ischemia, prevention of ischaemia or reperfusion injury, cyclosporin induced nephrotoxicity, glaucoma, radiocontrast nephropathy, diabetic neuropathy, allergy, restoration of organ perfusion in haemorrhagic shock, lipoprotein lipase related disorders, chronic obstructive pulmonary disease and hyaline membrane disease in newborn.
As used herein, the term xe2x80x9calkylxe2x80x9d is defined as a hydrocarbon radical of the general formula CnH2n+1. The alkane radical may be straight or branched. For example, the term xe2x80x9c(C1-C6)alkylxe2x80x9d refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, neopentyl, 3,3-dimethylpropyl, n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, 3-ethylbutyl, 4-methylpentyl, and other constitutional isomers containing 1 to 6 carbon atoms (including stereoisomers). The alkane radical may be unsubstituted or substituted with one or more substituents. For example, a xe2x80x9chalo-substituted alkylxe2x80x9d refers to an alkyl group substituted with one or more halogen atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, chloromethyl, bromomethyl, and the like). Similarly, the alkyl portion of an alkoxy, alkenyl or alkynyl group has the same meaning as alkyl defined above.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a fully hydrogenated nonaromatic carbocyclic ring where a hydrogen has been removed from one of the ring carbons. For example, (C3-C6)cycloalkyl includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9carylxe2x80x9d is defined as a single or multi-carbocyclic aromatic ring system where a hydrogen has been removed from the ring position of the arene nucleus. A multicyclic aromatic ring system may be fused (e.g., naphthyl) or non-fused (e.g., biphenyl). Unless specified otherwise, the ring system contains six to fourteen cyclic conjugated carbon atoms. Suitable aryl groups include phenyl, naphthyl, azulyl, anthryl, phenanthryl, benz[a]anthryl, and biphenyl. The aryl groups may be unsubstituted or substituted with one or more substituents (typically, 1 to 3 substituents). Suitable substituents include halo, CO2R9, OCOR9, OH, het4, S(O)pR11, (C1-C6)alkoxy, or (C1-C6)alkyl optionally substituted by OH, (C1-C6)alkoxy or halo.
The term heterocycle is defined as a fully saturated or partially unsaturated, single or multicyclic ring system wherein one or more of the rings contains 1-3 heteroatoms, each independently selected from N, O and S, and where a hydrogen has been removed from one of the ring positions of the nucleus. Unless specified otherwise, the heterocyclic ring system contains three to eight members. For example, a xe2x80x9c3- to 8-membered heterocyclexe2x80x9d includes groups such as epoxy, aziridinyl, 2H-pyrrolyl, 2H-imidazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, 1,3-oxathiolyl, 2H-pyranyl, 4H-pyranyl, 1,3-dioxinyl, piperazinyl, oxazinyl, isoxazinyl, morpholinyl and the like. The heterocycle may optionally be fused to a benzene ring (referred to herein as xe2x80x9cbenzofused heterocyclexe2x80x9d). For example, a 5- or 6-membered heterocycle fused to a benzene ring includes groups such as 2H-chromenyl, benzoxazinyl, and the like. Unless specified otherwise, the heterocyclic groups or benzofused heterocyclic groups may be substituted with 1 to 3 substitutions selected from the group consisting of halo, CO2R9, OCOR9, OH, unsubstituted heteroaryl, unsubstituted benzofused heteroaryl, S(O)pR11, (C1-C6)alkoxy, or (C1-C6) alkyl optionally substituted by OH, (C1-C6)alkoxy or halo).
The term xe2x80x9cheteroarylxe2x80x9d is defined as a five- or six-membered aromatic ring system containing 1-3 heteroatoms, each independently selected from N, O and S, where a hydrogen has been removed from one of the ring positions of the nucleus. For example, a 5- or 6-membered heteroaryl group includes furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl. The heteroaryl group may optionally be fused to a benzene ring (referred to herein as xe2x80x9cbenzofused heteroarylxe2x80x9d). Examples of 5- or 6-membered heteroaryl groups fused to a benzene ring include indolyl, benzothiophenyl, benzoxazolyl, anthranil, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and the like. Unless specified otherwise, the heteroaryl groups or benzofused heteroaromatic groups may be substituted with 1 to 3 substitutions selected from the group consisting of halo, CO2R9, OCOR9, OH, unsubstituted heteroaryl, unsubstituted benzofused heteroaryl, S(O)pR11, (C1-C6)alkoxy, or (C1-C6)alkyl optionally substituted by OH, (C1-C6) alkoxy or halo).
The term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo and iodo groups.
The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the patient being treated therewith.
The terms xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d, or xe2x80x9ctreatmentxe2x80x9d embrace both preventative (i.e., prophylactic) and palliative treatment.